Alzheimer's disease (AD) is a neurodegenerative disorder and the most common senile dementia. Three genes have been identified that mediate early onset familial AD: The amyloid precursor protein (APP), and presenilin 1 and 2. The deposition of amyloid beta peptide (Abeta) to the brain is the major pathological events leading to AD. Abeta is derived from APP by proteolytic processing via the sequential action of 2 proteases known as beta and gamma secretases. Presenilins are intimately associated with, if not they are, gamma secretase. Thus, identifying mechanisms by which gamma secretase activity and presenilins are regulated should lead to an increase in the understanding of AD pathogenesis and mechanisms of neurodegeneration. Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. Since many genes and signaling pathways are evolutionarily conserved, human homologs of these genes may provide insights for new diagnosis and treatment. The longterm goal of this work is to use the fly to identify regulators of gamma secretase activity, and translate the findings to study the pathogenesis of human AD. The Specific Aims of this proposal are to: 1) Use a functionbased gamma secretase reporter implemented in the fly eye as a background in which to screen for regulators of gamma secretase activity, 2) clone and characterize one or more of the genes identified during these screens. 3) identify human homologs of the genes identified in the screens. Begin the process of determining if mutations in these genes might serve a diagnostic purpose for identifying individuals at altered risk of developing AD.